**3.1 Hyperglycemia induced oxidative stress and inflammation**

Oxidative stress and inflammation are interlinked, as one causes another and vice versa, and they occur even under normal physiological conditions. However, these two phenomena last for a brief period as they are suppressed by intrinsic negative feedback mechanisms; increased production of antioxidants and antiinflammatory cytokines [19]. But, in certain chronic diseases like T2DM these altered states of internal environment sustain for a prolonged period as positive feedback mechanisms overrides the negative feedback mechanisms [19]. In addition, reduced parasympathetic nerve function due to autonomic dysfunction in T2DM leads to chains of inflammatory responses [20]. Thus, oxidative stress and inflammation are very prominent features in T2DM linked to both microvascular and macrovascular complications associated with T2DM [19]. Certain cells are particularly susceptible to hyperglycemic induced injury as their intracellular glucose concentration increases in a linear fashion with respect to the extracellular glucose level [16]. This is especially true for endothelial cells and neurons as the transport of glucose through their cell membranes is mediated by insulinindependent GLUTs [16].

Hyperglycemia induces overproduction of mitochondrial superoxide in endothelial cells of large and small blood vessels and neuronal axons [9, 16]. This leads to intracellular accumulation of reactive oxygen species (ROS) with subsequent activation of five major metabolic pathways: polyol pathway flux, increased formation of advanced glycation end-products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C (PKC) isoforms, and overactivity of the hexosamine pathway [9, 16]. Over activity of these five metabolic pathways leads to accumulation of toxic metabolic derivatives and pro-inflammatory substances, bringing about following consequences: vascular

endothelial damage, vasoconstriction, neuronal hypoxia, neuronal cell necrosis, neuronal apoptosis and axonal degeneration (**Figure 1**) [9, 16, 19, 21, 22].
